ESPE Abstracts

Background: Congenital isolated hypogonadotropic hypogonadism (СIHH) is a clinically and genetically heterogenous disorder characterized by absence or abnormal gonadotropin-releasing hormone secretion (GnRH). Adolescents with CIHH have complete or partial pubertal failure. Pathogenic variants in more than 60 genes have been associated with CIHH. CIHH can be complete, partial or reversal. Boys with CIHH may have micropenis and cryptorchidism. Except reproductive failure patients with CIHH can be diagnosed with deafness, cleft lip and palate, renal abnormalities, digital anomalies and etc. which is called non-reproductive phenotype. For some genes genotype-phenotype associations are confirmed.

Objective: To study genetic bases, to assess the prevalence of reproductive and non-reproductive features, to evaluate genotype-phenotype associations in Russian adolescents with CIHH.

Materials: 77 Russian adolescents with CIHH (62 boys, 15 girls) aged 13-17,9 years were included into the study. The diagnosis was made based on clinical and laboratory data. Data of associated congenital diseases were collected by survey. NGS sequencing of 53 genes, associated with CIHH, was provided in all the patients.

Results: Complete puberty failure was diagnosed in 80.5% CIHH patients. Reversal CIHH occurred in 5% of boys. 53% of girls had partial CIHH. Cryptorchidism occurred in 38.7% of CIHH boys. It was bilateral in 75% of them. Micropenis was diagnosed in 32.2% CIHH boys. Bilateral cryptorchidism and micropenis were diagnosed in every 8th CIHH boy. Hypospadias occurred in 3.2% CIHH boys. Non-reproductive phenotype was diagnosed in 38.9% CIHH adolescents: deafness (20.0%), heart defects (16.6%), cleft lip and palate (16.6%). Other patients had ichthyosis, CHARGE, renal, limbs and dental malformations. Pathogenic variants were diagnosed in 31% CIHH patients. Most frequently pathogenic variants occurred in genes GNRHR (26.3%), ANOS1 (21.0%) and FGFR1 (15.8%). Other pathogenic variants occurred in SEMA3A, CHD7, PROKR2, SOX10. Oligogenicity was diagnosed in 8.2% boys and 6.7% girls with CIHH. All patients with pathogenic variants in GNRHR (n = 8) had no non-reproductive phenotype. All patients (n = 6) with pathogenic variants in ANOS1 had complete puberty failure. 50% patients (3/6) with pathogenic variants in FGFR1 had cleft clip and palate/renal abnormalities/digital anomalies/deafness.

Conclusion: The majority of Russian adolescents with CIHH had complete failure of puberty. Partial CIHH occurred mostly in girls. Reproductive phenotype occurred in one third of boys with CIHH. Non-reproductive phenotype occurred in more than 30% CIHH patients also. The most common pathogenic genes were in genes GNRHR, ANOS1, FGFR1.